Brain degeneration in Huntington's disease caused by amino acid deficiency

March 26, 2014, Johns Hopkins University School of Medicine

Working with genetically engineered mice, Johns Hopkins neuroscientists report they have identified what they believe is the cause of the vast disintegration of a part of the brain called the corpus striatum in rodents and people with Huntington's disease: loss of the ability to make the amino acid cysteine. They also found that disease progression slowed in mice that were fed a diet rich in cysteine, which is found in foods such as wheat germ and whey protein.

Their results suggest further investigation into cysteine supplementation as a candidate therapeutic in people with the disease.

Up to 90 percent of the human corpus striatum, a brain structure that moderates mood, movement and cognition, degenerates in people with Huntington's disease, a condition marked by widespread motor and intellectual disability. And while the genetic mutation underlying Huntington's disease has long been known, the precise cause of that degeneration has remained a mystery.

In a report on their discovery in the advanced online publication of Nature on March 26, the Johns Hopkins researchers, led by Solomon Snyder, M.D., tracked the degenerative process to the absence of an enzyme, cystathionine gamma lyase, or CSE.

"Usually it's very hard, if not impossible, to develop straightforward mechanisms that explain what's going on in a disease. What's even harder is even if you can find a mechanism that causes a tissue to rot, usually there's nothing you can do about it," says Snyder, a professor of neuroscience at the Johns Hopkins University School of Medicine. "In this case, there is."

Huntington's disease, an inherited disorder, does its damage because of abnormal DNA coding for the amino acid glutamine. Healthy individuals have some 15 to 20 DNA "repeats" in that part of their genetic code, while Huntington's disease gene carriers have more than 36—and often upward of 100. Children born to a parent carrier have a 50/50 chance of inheriting the disorder, and the greater the number of repeats, the earlier the age of onset of the incurable disorder.

Bindu Diana Paul, Ph.D., a molecular neuroscientist and faculty instructor in Snyder's laboratory, was studying mice lacking CSE, which helps make the and hydrogen sulfide that moderate blood pressure and heart function. Paul, who had previous research experience with Huntington's disease, says she was startled to observe that her mutant mice also behaved a lot like those with the disease.

When a normal mouse is dangled upside down from its tail, it will twist and turn and try to bite the offending hand, she explains. But her CSE-knockout mice stayed relatively still and clasped their paws together—the same behavior she'd observed in mice with the rodent equivalent of Huntington's disease. "It looked like there was a neurological deficit," Paul says. "But nobody had looked at CSE in the brain."

Paul and Snyder began monitoring CSE in mouse and human brain tissues and found considerably less CSE in all diseased tissues. All people carry some normal huntingtin protein made by the Huntington's disease gene, although the protein's function remains elusive. But people with Huntington's disease also carry mutant huntingtin proteins. Snyder and his team saw that the mutant proteins were attaching themselves to a crucial protein responsible for turning the CSE gene on or off, which ultimately led the diseased rodent and human brain tissues to be deprived of cysteine.

To see if loss of cysteine was directly responsible for the symptoms associated with Huntington's disease, the Johns Hopkins team turned to readily available sources of the substance in everyday foods and fed mice a cysteine-rich diet.

The results, Paul says, were striking. When those mice were dangled from their tails, they resumed struggling, although with a bit less vigor than their healthy peers. They were able to grip an object with greater strength, and they took longer to fall off a balancing apparatus than CSE-knockout mice. Their life expectancies increased one to two weeks.

Snyder and Paul say they are cautiously optimistic about the results, noting that although they suggest a possible treatment for Huntington's disease, it's clear that a high cysteine diet merely slows rather than halts the progression of the disease. Moreover, the results in live mice may not occur in humans.

Explore further: Drug reduces brain changes, motor deficits associated with Huntington's disease

More information: Paper: dx.doi.org/10.1038/nature13136

Related Stories

Drug reduces brain changes, motor deficits associated with Huntington's disease

November 26, 2013
A drug that acts like a growth-promoting protein in the brain reduces degeneration and motor deficits associated with Huntington's disease in two mouse models of the disorder, according to a study appearing November 27 in ...

Research reveals new therapeutic targets for Huntington's and Parkinson's disease

March 14, 2014
(Medical Xpress)—Research from Western University has revealed a possible new target for treating movement disorders such as Huntington's disease (HD) and Parkinson's disease. Stephen Ferguson, PhD, a scientist at Western's ...

New therapeutic target identified for Huntington's disease

November 26, 2013
A new study published 26th November in the open access journal PLOS Biology, identifies a new target in the search for therapeutic interventions for Huntington's disease – a devastating late-onset neurodegenerative disorder.

Scientists identify new Huntington disease pathway

February 19, 2014
(Medical Xpress)—An international group of researchers has identified a major new pathway thought to be involved in the development of Huntington disease. The findings, published in the Proceedings of the National Academy ...

Researchers track Huntington's disease progression using PET scans

August 29, 2013
Investigators at The Feinstein Institute for Medical Research have discovered a new way to measure the progression of Huntington's disease, using positron emission tomography (PET) to scan the brains of carriers of the gene. ...

Recommended for you

Your brain responses to music reveal if you're a musician or not

January 23, 2018
How your brain responds to music listening can reveal whether you have received musical training, according to new Nordic research conducted in Finland (University of Jyväskylä and AMI Center) and Denmark (Aarhus University).

New neuron-like cells allow investigation into synthesis of vital cellular components

January 22, 2018
Neuron-like cells created from a readily available cell line have allowed researchers to investigate how the human brain makes a metabolic building block essential for the survival of all living organisms. A team led by researchers ...

Finding unravels nature of cognitive inflexibility in fragile X syndrome

January 22, 2018
Mice with the genetic defect that causes fragile X syndrome (FXS) learn and remember normally, but show an inability to learn new information that contradicts what they initially learned, shows a new study by a team of neuroscientists. ...

Epilepsy linked to brain volume and thickness differences

January 22, 2018
Epilepsy is associated with thickness and volume differences in the grey matter of several brain regions, according to new research led by UCL and the Keck School of Medicine of USC.

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.